Obesity and diabetes are more common in African-Americans than whites. Because free fatty acids (FFA) participate in the development of these conditions, studying race differences in the regulation of FFA and glucose by insulin is essential. Objective: The objective of the study was to determine whether race differences exist in glucose and FFA response to insulin. Design: This was a cross-sectional study. Setting: The study was conducted at a clinical research center. Participants: Thirty-four premenopausal women (17 African-Americans, 17 whites) matched for age 36 10 yr (mean sd) and body mass index (30.0 6.7 kg/m(2)). Interventions: Insulin-modified frequently sampled iv glucose tolerance tests were performed with data analyzed by separate minimal models for glucose and FFA. Main Outcome Measures: Glucose measures were insulin sensitivity index (S(I)) and acute insulin response to glucose (AIRg). FFA measures were FFA clearance rate (c(f)). Results: Body mass index was similar but fat mass was higher in African-Americans than whites (P < 0.01). Compared with whites, African-Americans had lower S(I) (3.71 1.55 vs. 5.23 2.74 10(-4) min(-1)/(microunits per milliliter) (P = 0.05) and higher AIRg (642 379 vs. 263 206 mU/liter(-1) min, P < 0.01). Adjusting for fat mass, African-Americans had higher FFA clearance, c(f) (0.13 0.06 vs. 0.08 0.05 min(-1), P < 0.01). After adjusting for AIRg, the race difference in c(f) was no longer present (P = 0.51). For all women, the relationship between c(f) and AIRg was significant (r = 0.64, P < 0.01), but the relationship between c(f) and S(I) was not (r = -0.07, P = 0.71). The same pattern persisted when the two groups were studied separately. Conclusion: African-American women were more insulin resistant than white women, yet they had greater FFA clearance. Acutely higher insulin concentrations in African-American women accounted for higher FFA clearance. We are investigating the effects of beta-blockers on model parameters, testing the bf hypothesis that changes in insulin action on plasma FFA may be correlated with the efficacy of these drugs (collaboration with Beitelshees, University of Maryland). Furthermore, we are testing the hypothesis that the efficacy of TZDs in obese subjects is correlated with changes in parameters in the mathematical model of insulin action on lipolysis (collaboration with Snitker, University of Maryland).